5,5-Dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5h-{8 1{9 -benzopyrano{8 3,4-d{9 pyridine as a sedative hypnotic

ABSTRACT

A method of inducing and maintaining sleep in a mammalian patient in need of such treatment comprising administering a therapeutically effective amount of 5,5-dimethyl-10-hydroxy-8-(3methyl-2-octyl)-2-(2-propynyl)-1,2,3,4 -tetrahydro-5H(1)benzopyrano(3,4-d)pyridine to said patient.

United States Patent 1191 Harris et al.

[ 5,5-DIMETHYL-l0-l'lYDROXY-8-(3- METHYL-2-OCTYL)-2-(2-PROPYNYL)- l,2,3,4-TETRAHYDRO-5l-l-[ l BENZOPYRANO[3,4-D]PYRIDlNE AS A SEDATIVE HYPNOTIC [75] lnventors: Louis Selig l-larris, Richmond, Va.; Harry George Pars, Lexington, lll.; Raj Kumar Razdan, Belmont, lllx, Anthony Thomas Dren, Waukegan,

Ill.

[73] Assignee: Sharps Associates, Cambridge,

Mass.

22 Filed: May 3, 1974 21 Appl. No.: 466,541

Related U.S. Application Data [63] Continuation-in-part of Ser. No. 283,436, Aug. 24,

[52] U.S. Cl. 424/263 1451 May 13, 1975 Primary Examiner-Stanley J. Friedman Attorney, Agent, or FirmMerriam, Marshall, Shapiro & Klose [57] ABSTRACT A method of inducing and maintaining sleep in a mammalian patient in need of such treatment comprising administering a therapeutically effective amount of 5,5-dimethyl-l0-hydroxy-8-(3-methyl-2- octyl)-2-( 2 propynyl 1 ,2,3,4-tetrahydro-SH- [l]benzopyrano[3,4-d]pyridine to said patient.

2 Claims, No Drawings 1 5.5-DIMETHYL-l-HYDROXY-8-(3-METHYL-2- OCTYL)-2-(2-PROPYNYL)-l,2,3,4-TETRAHYDRO- SH-[l l-BENZOPYRANO[3,4-D1PYRIDINE AS A SEDATIVE HYPNOTIC RELATED APPLICATION This application is a continuation-in-part of our copending application Ser. No. 283.436 filed Aug. 24. I972.

BACKGROUND OF THE INVENTION Sleep is no longer regarded as a single homogeneous behavioral state. Through continuous all night recordings of EEG patterns and other physiologic activity. the existence of two distinct component stages of sleep have been revealed in lower animals and in man: slowwave sleep with high voltage. slow-wave neocortical activity; and fast-wave sleep with low voltage. fast-wave neocortical EEG activity and rapid eye movements. Several substages of slow-wave sleep have also been recognized and include a spindal wave pattern associated with a drowsy behavioral state. Fast wave sleep is also known as paradoxical sleep or rapid eye movement sleep (REM) and has been associated with dreaming in man.

There are a number of known agents which induce and maintain sleep in man. One of the common barbituates. pcntobarbital. increases total sleep time. increases the light stages of sleep. i.e.. stage II sleep and decreases the deeper stages. i.e.. stages III and IV. This generally is the pattern for most of the currently available sedative hypnotics. One of the problems with the currently available sedative hypnotics is that the patient often feels drugged and in a stupor when he awakes.

It is presently thought that a compound which increases slow-wave sleep time without disturbing REM sleep would be a highly desirable sedative hypnotic agent. The present invention provides such a compound.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method of inducing and maintaining sleep using 5.5-dimethyllU-hydroxy-S- (3-methyl-2-octyl 2-( Z-propynyl l .Z.3.4-tetrahydro- 5H-[ 1 ]ben7.opyrano[3.4-djpyridine as the sedative hypnotic.

5.5-Dimethyl'ltJ-hydroxy8-(3-methyl-2-octyl)-2- (Z-propynyl )-l .2 ,3.4-tetrahydro5H- l lbenzopyranol3.4d}pyridine has previously been reported to be useful as a central nervous system depressant (See US. Pat. No. 3.576.798). However. its use as a sedative hypnotic had not previously been recognized. It has now been found that the compound increases slow-wave sleep without interrupting REM sleep and is useful a sedative hypnotic in mammalian patients. including lower animals and man.

The compound useful in the practice of this invention is represented by the formula (iTH -C:CH N

The compound can be prepared according to the method taught in U.S. Pat. No. 3.576.798.

Generally speaking. 5.5 dimethyl-lll-hydroxy-8 (3-methyl-2-octyl 2-( 2-propynyl )-l .2.3.4-tetrahydro- SI-H 1 lbenzopyranol3.4-dlpyridine is useful as a sedative hypnotic when administered to human patients in need of such treatment in dosages from 0.01 to 25.0 mg per day and generally ()5 to I15 mg per day. The exact dosage administered should, of course. be prescribed by a physician. In lower animals. the dosage could be about 0.01 to I mg/kg of body weight. Regardless of the size or species of mammal treated. the dosage administered. of course. should be one which induces a sedative hypnotic effect. i.e.. induces and/or prolongs sleep. without significantly reducing REM sleep.

The compound can be administered orally or parenterally to a human or a lower animal. Oral administration in the form of a tablet. capsule or liquid containing the compound. is preferred. Intravenousadministration of the compound in a suitable liquid is also satisfactory.

While it is preferred that the compound be administered at bedtime. in the case of a hospitalized patient or other patient whom needs to be sedated. the com pound can be administered in divided doses or at different times during the day.

The sedative hypnotic activity of the compound useful in the practice of this invention was initially evaluated in cats and monkeys by a qualitative analysis of the EEG patterns recorded on a polygraph. Changes in total sleep times and in the EEG stages of the sleep were measured.

The following example further illustrates this inven tron:

EXAMPLE Two adult male cats and three adult rhesus monkeys (male) were prepared surgically with chronic indwelling electrodes to monitor cortical EEG potentials. eye movements (EOG) and neck muscle potentials (EMG). The animals were acclimated to dimly lit. sound attenuated experimental chambers with white noise provided to mask unwanted external sounds. The chambers were located in special rooms and had a plexiglass door to allow close observation of gross behavior on closed circuit television.

All experimental sessions began at approximately 5 P.M. and had a duration of at least l4 hours. The animals were routinely fed at the start of the session and polygraph recordings were made continuously thereafter through the night. To administer the compound orally to the cats. the compound was mixed in the cat food which was presented at the usual feeding time. The food was generally consumed within 15 or 20 minutes. For oral administration to the monkeys. the drug powder was placed inside a slice of apple or was suspended in 0.5 percent Methocel methylcellulose and- /or Hawaiian Punch drink and given from a syringe with an oral feeder needle.

The cats were left undisturbed during the experimental session but the monkeys were awakened at approximately 45 minute intervals by applying mild electroshock to the neck muscle electrodes. The purpose of the periodic awakening of the monkeys was to produce a disturbed sleep pattern and simulate a state of insomnia. Effects produced by a single dose administration of the compound were determined in both species. In addition, the effects of repeated administration for 5 days was studied in one monkey. In the single dose studies,

a three day protocol was followed: day l, adaptation; day 2. vehicle control (placebo); day 3, one dose of drug. Each animal served as its own control. ln the repeat dose study. the protocol was as follows: day l ad aptation; days 2 and 3, vehicle controls (placebo); days 4-8, 5 consecutive days of drug administration; days 1-10. vehicle (placebo). On control days, the vehicle was administered without drugs added.

Polygraph recordings were evaluated visually with an established set of criteria to quantify changes in sleepwaking patterns (Lanoira and Killam: Electroencephv Clin. Neurophysiol. 25: 530-542, (I965); Jewctt and Norton: Exper. Neurol. 463-474, U966). Each 1- minute segment of the polygraph tracings was identified as one of the following stages: (A) awake; (B) spindle sleep (drowsy): (C) slow-wave sleep; (D) REM sleep. Calculations were made from the data from the following parameters: (A) total sleep time (as minutes and as percentages of total session time); and (B) amount of time in spindle sleep. slow-wave sleep and REM sleep (as minutes, percentage of total session time and as percentage of total sleep time).

The compound useful in the practice of this invention produced EEG and behavioral effects indicative of sedative hypnotic activity. The EEG pattern in both cats and monkeys showed increased amounts of high voltage. slow-wave activity that was associated with beha ioral sleep. Although the animals appeared to sleep for greater periods of time after the drug, they could be easily aroused.

in the cat. the compound produced an increase in total sleep time minutes at dosages of O. l to [.0 mg/kg. The principal effect of the compound useful in the practice of this invention of the EEG stages of sleep to account for the increase in total sleep time was a marked increase in slow-wave sleep. This effect was associated with a decrease of spindle sleep. REM sleep did not change consistently, but a slight increase was noted. Similar effects were noted in the monkey at dosages of l to 2.0 mg/kg.

In the 5-day study, the effects produced by a 2 mg/kg oral dose on total sleep time and EEG stages of sleep in a monkey were evaluated. The compound produced qualitatively the same effects on each of the five days of repeated administration as described above in the acute studies. However, there was no trend toward any accumulative effect developing over the Sday period.

The compound useful in the practice of this invention can be formulated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills and the like for immediate or sustained release, by combining the compound with a suitable pharmaceutically acceptable carrier or diluent according to meth ods well known in the art. Such dosage forms may additionally include lubricants, excipients, binders, fillers, flavoring and sweetening agents and other therapeutically inert ingredients necessary for the formulation of the desired preparation.

The foregoing detailed description has been given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications will be obvious to those skilled in the art.

We claim:

1. A method of inducing and/or prolonging sleep, without significantly reducing REM sleep, comprising administering a therapeutically effective amount of 5,- S-dimethyllO-hydroxy 8-( 3-methyl-2-octyl)-2-( 2- propynyl)-l ,2,3,4-tetrahydro-5H-[ l ]benzopyrano[ 3 ,4- d]pyridine to a mammalian patient.

2. The method of claim 1 wherein said compound is administered orally to said patient in a dosage of from 0.01 to 25.0 mg. daily. 

1. A METHOD OF INDUCING AND/OR PROLONGING SLEEP, WITHOUT SIGNIFICANTLY REDUCING REM SLEEP, COMPRISING ADMINISTERING A THERAPEUTICALLY EFFECTIVE AMOUNT OF 5,5:DIMETHYL-10-HYDROXY8-(3-METHYL-2-OCTYL)-2(2-PROPYNYL)-1,2,3,4-TETRAHYDRO-5H(1)BENZOPYRANO(3,4-D)PYRIDINE TO A MAMMALIAN PATIENT.
 2. The method of claim 1 wherein said compound is administered orally to said patient in a dosage of from 0.01 to 25.0 mg. daily. 